Processes and composition for remineralization and prevention of demineralization of dental enamel

ABSTRACT

The present invention relates to the problems of remineralization without demineralization of dental enamel by applying to the teeth a composition which is present in two phases which do not react with one another until introduced into the oral cavity. One phase contains at least one water-soluble calcium compound and the other contains at least one water-soluble inorganic phosphate and at least one water-soluble fluorine compound. In this way the ions which effect remineralization can be absorbed by the dental enamel and their subsequent reaction causes rehardening of demineralized areas in the dental enamel.

This application is a division of application Ser. No. 465,875, filedJun. 6, 1995, now U.S. Pat. No. 5,605,675.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to processes and compositions which are useful torapidly remineralize subsurface dental enamel. More specifically, thisinvention relates to salt solutions, such as calcium and phosphate saltsolutions, which are applied to lesions in dental enamel resulting inremineralization of subsurface dental enamel and/or mineralizing tubulesin dentin thereby counteracting caries and/or hypersensitivity.

2. The Prior Art

The primary component of the enamel and dentin in teeth is calciumphosphate in the form of calcium hydroxyapatite. This material is highlyinsoluble at normal oral pHs. However, carious lesions form in teeth,when they are subjected to acids produced from the glycolysis of sugarsby the action of various oral bacteria. This is because calciumphosphate salts are more soluble in acidic media.

Saliva is supersaturated with respect to calcium and phosphate ions.Saliva therefore helps protect teeth against demineralization and canslowly remineralize teeth which have become demineralized by acids. Itis well known that the presence of fluoride ions can enhance the naturalremineralization process and this is one of the accepted mechanisms bywhich fluoride toothpastes and rinses protect against caries. Theefficacy of fluoride containing toothpastes and rinses to remineralizeteeth is limited by the modest levels of calcium and phosphate insaliva. It is evident from the prior art that it is highly desirable toincrease the available concentration of calcium and phosphate ions inthe oral cavity to speed up the remineralization process. However,because of calcium phosphate's low solubility at the pH of saliva theaddition of higher levels of dissolved calcium and phosphate ions is noteasily accomplished.

Remineralization of dental enamal has been carried out experimentallyboth in vivo and in vitro. Some studies have concentrated on theremineralizing properties of saliva and synthetic solutionssupersaturated with respect of hydroxyapatite. Such studies comprise thesubject matter of U.S. Pat. Nos. 3,679,360 (Rubin) and 4,097,935(Jarcho).

Generally, the supersaturated solutions or slurries used in thesepatents for remineralization experiments have been prepared from asingle form of calcium phosphate. When a caries lesion is flooded withone of these supersaturated solutions, the calcium and phosphate ions inthe form of precipitated hydroxyapatite remineralize the lesion.

However, these solutions are impractical for use for several reasons.First, the amount of calcium and phosphate ions available forremineralization in these supersaturated solutions is too low. It isreported that it takes approximately 10,000 unit volumes of the usualsupersaturated solution to produce one unit volume of mineral. Thus,remineralization by this method requires both an excessive volume offluid and an excessive number of applications. The supersaturatedsolutions are inherently limited in this respect because they cannotmaintain their supersaturated state. When the hydroxyapatiteprecipitates out to the point where the solution is no longersupersaturated, new supersaturated solution must be introduced or theremineralization process stops.

Another problem with single calcium phosphate slurries is that as thehydroxyapatite precipitates out of solutions the pH of the solutionchanges. Unless the old solution is removed from contact with the toothmaterial, the solution may become too acidic or alkaline and damage thedental tissue.

U.S. Pat. No. 4,080,440 (Digiulio et al) discloses a metastable solutionof calcium and phosphate ions at a low pH (between 2.5 to 4.0)underwhich conditions the solubility of calcium phosphate salts is high.After penetration of the solution into demineralized enamel,remineralization results from the precipitation of calcium phosphatesalts when the pH rises. Fluoride ions can be included in the metastablesolution. A significant disadvantage of the use of metastable solutionsis that the relatively low pH might demineralize the dental enameland/or injure other tissue.

U.S. Pat. Nos. 4,177,258 and 4,183,915 (Gaffar et al) provide for aremineralizing solution containing supersaturated concentrations ofcalcium ions, phosphate ions and a fluoride source stabilized by thepresence of an antinucleating agent such as diaminetetramethylenephosphonic acid. This solution is preferably adjusted tothe neutral pH range where it is alleged to most effectivelyremineralize sub-surface lesions. Even though the antinucleating agentwould be expected to stabilize the solution, equilibrium of thesupersaturated concentrations is still found difficult to maintain andavoid precipitation of hydroxyapatite and changes in the pH of thesolution

U.S. Pat. Nos. 4,083,955 (Grabenstetter et al) and 4,397,837 (Raaf etal) provide a process for remineralizing demineralized enamel by theconsecutive treatment of tooth surfaces with separate solutionscontaining calcium ions and phosphate ions. In this process fluorideions may be present in the phosphate solutions. It is immaterial whichionic solution is used to treat the teeth first. By sequentiallyapplying calcium and phosphate ions to the tooth surface highconcentrations of the ions are able to penetrate into lesions insolution form, where they precipitate as a calcium phosphate salt whenions from the second treatment solution diffuse in. While apparentlysuccessful this method involves the inconvenience of a plurality ofsequential applications which can also be found to be time consuming.

Another problem with known remineralization techniques is that theremineralization may stop before the lesion is completely remineralizeddue to build up of the remineralized tooth material in or on the outerlayer of the tooth's surface. This build up occurs when the rate ofremineralization is too fast and prevents the diffusion of the mineralinto the deeper regions of the lesion, thus thwarting the fullremineralization of the tooth.

There is a need for a method of remineralizing dental enamel that doesnot require excessive amounts of solution and inordinately long orfrequent exposure times.

It is the object of the present invention to provide a process andespecially a composition for the remineralization and the prevention ofdemineralization of human teeth, which process and composition arecapable of effectively incorporating calcium ions, phosphate ions andfluoride ions into the dental enamel, the composition also being easilyusable by the consumer and not differing significantly, in flavor andappearance, from customary dental cosmetics.

SUMMARY OF THE INVENTION

In accordance with the present invention the problems ofremineralization, without demineralization are solved by applying to theteeth a composition which is present in two phases which do not reactwith one another until introduced into the oral cavity. One phasecontains at least one water-soluble calcium compound and the othercontains at least one water-soluble inorganic phosphate and at least onewater-soluble fluorine compound. In this way the ions which effectremineralization can be absorbed by the dental enamel and theirsubsequent reaction causes rehardening of demineralized areas in thedental enamel.

It has been found that effective remineralizing treatments can beprepared by directly combining solutions or preparations with solublesalts containing high concentrations of calcium, phosphate and fluorideions and applying them to teeth at moderate pHs. However, the calciummust be prevented from the reaction with the phosphate ions or fluorideions until immediately before use. This can be accomplished by providinga dual container or tube system in which the calcium ions are in adifferent container or tube than the phosphate or fluoride ions or byincorporating undissolved soluble salts containing these ions into asingle base in which the ions are separated physically, e.g., by theencapsulation of at least one or are insoluble in said base.

For two part systems, two part toothpastes, gels, professional gels,i.e., those which are applied professionally or are obtained by aprescription, mouthwashes, and the like are prepared, wherein part Icontains from about 0.05% to about 15% water-soluble calcium salt, andpart II contains from about 0.05% to 15% water-soluble phosphate saltand from about 0.01% to 5% fluoride releasing agent such that when thetwo parts are mixed the pH is between about 4.5 and 10.0, andpreferrably between about 5.5 and 7.0. The two parts are mixed andimmediately applied to the teeth being treated. It has been found thatsuch combinations produce rapid remineralization of lesions and are muchmore effective than conventional fluoride containing toothpastes inremineralizing teeth.

The compositions of the invention give substantially improvedremineralization and prevention of demineralization of human teeth ascompared with prior art compositions.

The disadvantages of the prior art methods are overcome by the presentinvention which effects subsurface remineralization rather than surfaceremineralization. Since dental caries begins as a subsurfacedemineralization of the dental enamel, subsurface remineralizationarrests and repairs the carious lesion before any permanent structuraldamage to the tooth occurs. The present invention does not requirepreparation of the enamel surface, capping of the tooth, or removal ofdecay products. Further, the present invention may be convenientlypracticed by the public without substantially changing their dental carehabits.

DESCRIPTION OF THE INVENTION

The present invention lies in the discovery that dental enamel may beremineralized by the application of certain soluble salts yielding ionswhich will react to form a desirable remineralizing precipitate. Theapplication consists of the simultaneous use of a two part systemwherein the first part is a reactant paste, gel or solution of a solublesalt which is placed in contact with the tooth surface. In this firstreactant part are selected cations with diffuse through the toothsurface to its demineralized subsurface. In the second part a reactantpaste, gel or solution containing selected anions is placedsimultaneously in contact with the tooth surface. The anions diffusethrough the tooth surface to the demineralized subsurface with thecations and form a precipitate which is bound to the tooth structure. Asa results the tooth's subsurface is remineralized when an effectiveamount of the two part system is utilized.

By "effective amount of remineralizing system or agent" is meant anamount when used in accordance with this invention will bring about theremineralizing of teeth having caries lesions, or the mineralizing ofnormal teeth to prevent caries from forming by utilizing a toothpaste,gel, or mouthwash having the various components in the amounts set forthbelow.

Concentrations of the soluble salt are from about 0.05 to 15% or thelimit of solubility of the salt. Excess salt can be presents if desired.Concentrations from about 0.10% to 10% are preferred. The concentrationsof the soluble salts containing the desired anions are essentially thesame as those for the water-soluble salts containing the desiredcations.

Although many precipitates are within the broad scope of this invention,by depositing a precipitate less soluble than the original enamel, theremineralized subsurface can be made to be more resistant todemineralization than was the original enamel. Due to the presence of afluoride ion, the remineralized enamel is more resistant todemineralization than was the original enamel. The concentration of saltcontaining fluoride ion in the solution may be from about 0.01% to 5.0%,but from about 0.02% to 2.0% is preferred.

In order to effect remineralization of the dental enamel, an effectiveamount of the desired cations and anions must be employed in the oralcavity. The amount of solution placed in the mouth must contain at least100 ppm of desired cations and 250 ppm of desired anions and preferablycontains more than 3,000 ppm of desired cations and 3,000 ppm of desiredanions. It is preferred to provide a level of fluoride ions betweenabout 20 ppm to 5,000 ppm in the oral cavity from the dentifrice orprofessionally applied or prescribed gel.

While the length of time of contact between the dissolved salts and thetooth's surface is not critical, it is necessary for the length of timeto be great enough to allow diffusion of the ions through the tooth'ssurface to the demineralized subsurface. It is submitted that at leastten seconds is required for this diffusion and preferably it should begreater than thirty seconds.

Each solution should have a pH of from about 4.5 to 10.0 and preferablybetween about 5.5 and 7.0 before and after the precipitation reaction,and be otherwise compatible in the oral environment. While someprecipitation may occur, not all of the ions should combine prematurelyin the solution to form a precipitate, but must be able to diffusethrough the surface of the tooth to a demineralized subsurface area andbe able to form an insoluble salt with ions of the other solution.

The solutions and the insoluble precipitates must have acceptable levelsof toxicity (i e., the particular ions, in the amounts used in theremineralization process, must be non-toxic).

In the preferred embodiment of the present inventions the remineralizingcationic solution contains about 0.05% to 15%, preferably about 0.10% to10% of a dissolved calcium salt yielding calcium ions. Theremineralizing anionic solution contains from about 0.05% to 15%,preferably about 0.10% to 10%, of dissolved phosphate salt yieldingphosphate ions and from about 0.01% to 5.0%, preferably from about 0.02%to 2.0%, of a soluble fluoride salt yielding fluoride ions.

The resulting precipitate is a calcium phosphate or hydroxyapatite, thenatural constituent of tooth enamel, with incorporated fluoride ions.Not only does this process result in remineralized enamel, but theremineralized enamel may be more resistant to subsequentdemineralization than was the original enamel.

As the calcium compound it is, in principle, possible to employ, in thepreparations of the invention, all water-soluble toxicologicallyharmless calcium compounds. A compound is considered to be water-solublewhen at least 0.25 gram thereof dissolves in 100 ml of H₂ O at 20° C.

Suitable water-soluble calcium compounds are, for example, calciumchlorides calcium nitrate, calcium acetate, calcium gluconate, calciumbenzoate, calcium glycerophosphate, calcium formate, calcium fumarate,calcium lactate, calcium butyrate and calcium isobutyrate, calciummalate, calcium maleate, calcium propionate, calcium valerate ormixtures of water-soluble calcium compounds. Calcium nitrate ispreferred. In the compositions of the invention for the remineralizationof human dental enamel, at least about 100 ppm of calcium ions should bepresent; the upper limit is about 35,000 ppm of calcium ions.

Suitable water-soluble inorganic phosphates within the scope of thepresent invention are, for example, monobasic-calcium phosphate,dipotassium phosphate, sodium meta-phosphate, monosodium phosphate andthe alkali salts and ammonium salts of orthophosphoric acid, such aspotassium, sodium or ammonium orthophosphate. monobasic-calciumphosphate and dipotassium phosphate are preferred. The concentration ofthe phosphate ions is preferably about 250 to 40,000 ppm; solubility inwater is defined as in the case of the calcium compounds.

If desired, water-soluble salts yielding both calcium and phosphateions, such as monobasic-calcium orthophosphate, may be employed. Thecompositions of the invention for the remineralization or prevention ofdemineralization of human teeth also contain water-soluble fluoridecompounds, the caries-prophylactic activity of which has for a long timebeen considered to be established. These compounds are preferablypresent in the phase containing phosphate in order to avoid theformation of sparingly soluble calcium fluoride.

Suitable fluoride compounds are the alkali fluorides such as sodium,potassium, lithium or ammonium fluoride, tin fluoride, indium fluoride,zirconium fluoride, copper fluoride, nickel fluoride, palladiumfluoride, fluorozirconates such as sodium, potassium or ammoniumfluorozirconate or tin fluorozirconate, fluorosilicates, fluoroborates,fluorostannites.

Organic fluorides, such as the known amine fluorides are also suitablefor use in the compositions of the invention.

Water-soluble alkali metal monofluorophosphates such as sodiummonofluorophosphate, lithium monofluorophosphate and potassiummonofluorophosphate, preferably, sodium monofluorophosphate may beemployed. In addition other water-soluble monofluorophosphate salts maybe employed including ammonium monofluorophosphate aluminummonofluorophosphate, and the like. If monofluorophosphate salts are usedas the fluoride source, they could be present in the first componentalong with the calcium cations without departing from the presentinvention. However, this is less desirable due to the potential loss offluoride.

Suitable toothpastes and gels can be made by employing in both theanionic and cationic portions of the toothpaste, from about 0.5% to 50%,preferably from about 5% to 25%, of an abrasive, from about 0.2% to 5%of a sudsing agent, from about 0.1% to 5% of a binding agent, from 0% to50% of a humectant, and the balance, water and minors.

The pH of a component part of the toothpaste or gel containing theactive cationic ingredients preferably has a pH of more than about 3.The mixture of the two portions which is placed in the mouth, however,must have a pH of from about 4.5 to about 10.0 and, preferably, betweenabout 5.5 and 7.0. The pH's of the cationic portion and the anionicportion can be adjusted so long as the above parameters are notexceeded.

Suitable abrasives include silica xerogels. Other conventionaltoothpaste abrasives can be used in the compositions of this invention,and include beta-phase calcium pyrophosphate, dicalcium phosphatedihydrate, anhydrous calcium phosphate, calcium carbonate, zironiumsilicate, and thermosetting polymerized resins. Silica aerogels and theinsoluble metaphosphates such as insoluble sodium metaphosphate can beused. Mixtures of abrasives can be also be used. Silica xerogelabrasives are preferred.

Suitable sudsing agents are those which are reasonably stable and formsuds throughout the period of application. Preferably, non-soap anionicor nonionic organic synthetic detergents are employed. Examples of suchagents are water-soluble salts of alkyl sulfate having from 10 to 18carbon atoms in the alkyl radical, such as sodium lauryl sulfateswater-soluble salts of sulfonated monoglycerides of fatty acids havingfrom 10 to 18 carbon atoms, such as sodium monoglyceride sulfonate,salts of C₁₀ -C₁₈ fatty acid amides of taurine, such as sodium N-methyltaurate, salts of C₁₀ -C₁₈ fatty acid esters of isethionic acids andsubstantially saturated aliphatic acyl amides of saturatedmonoaminocarboxylic acids having 2 to 6 carbon atoms, and in which theacyl radical contains 12 to 16 carbon atoms, such as sodium-N-laurylsarcoside. Mixtures of two or more sudsing agents can be used.

A binding material is added to thicken and provide a desirableconsistency for the present compositions. Suitable thickening agents arewater-soluble salts of cellulose ethers, such as sodium carboxymethylcellulose, hydroxypropyl cellulose, and hydroxyethyl cellulose. Naturalgums such as gum karaya, gum arabic, carrageenan and gum tragacanth, canalso be used. Colloidal magnesium aluminum silicate, silica aerogels,silica xerogels, fumed silica, or other finely divided silica can beused as part of the thickening agent for further improved texture. Apreferred thickening agent is xanthan gum.

It is also desirable to include some humectant material in a toothpasteor gel to keep it from hardening. Suitable humectants include glycerine,sorbitol, polyethylene glycol, propylene glycol, and other ediblepolyhydric alcohols as well as mixtures thereof.

Toothpaste or gel compositions may also contain flavoring agents such asoil of wintergreen, oil of pepperment, oil of spearmint, oil ofsassafras, and oil of clove. Toothpaste or gel compositions may alsocontain sweetening agents such as saccharin, dextrose, levulose, sodiumcyclamate, and aspartame Mixtures of sugar with a sweetner, e.g.,sucralose, are contemplated.

It is, of course, also possible to manufacture one or both phases in theform of a transparent gel, the gel-forming agents to be used includingknown thickeners, for example the alkali salts of polyacrylic acid, andalso preferentially dehydrated silicon dioxide gels of particle sizeabout 2 to 20 microns and specific surface area about 200 to 900 m² /g.

The remineralizing systems herein can also be provided in the form of amouthwash product. Both the cationic and anionic parts of mouthwashescan be made in accordance with the following. Mouthwashes generallycomprise an aqueous solution of ethyl alcohol and flavoring materials.The alcohol provides an antibacterial effect, solubilizes the flavoringmaterials and provides a pleasant mouth feeling. Alcohol-freemouthwashes are now, however, gaining in popularity. Optionally,mouthwashes also contain additional antibacterial agents and humectantssuch as glycerine and sorbitol which give a moist feeling to the mouth.

Typically, mouthwashes contain about 0 to 30%, preferably about 0 to20%, ethyl alcohol; about 30% to 90% water; about 0 to 20% glycerine orother humectant; about 0 to 0.1% of an antibacterial agent; about 0 to0.2% of a soluble fluoride source, about 0.01% to 0.5% of a sweeteningagents about 0.01% to 2.0% of a flavoring agent, and from about 0.1% to1% of an emulsifier-surfactant.

Examples of suitable flavoring agents include heliotropyl nitrile,wintergreen oil (methyl salicylate), oil of peppermint, oil of assia,oil of anise, oil of cinnamon, and mixtures thereof. Suitable sweeteningagents include saccharin, glycerine, sorbitol, levulose, and6-(tribluoromethyl)-tryptophane and aspartyl phenylalanine methyl ester.

In one embodiment of this invention there is provided a product forremineralizing dental enamel comprising: (i) a first componentcomprising from about 0.05% to 15.0%, preferably about 0.10% to 10%,water-soluble calcium salt; (ii) a second component comprising fromabout 0.05% to 15.0%, preferably about 0.10% to 10% water-solublephosphate salt together with from about 0.01% to 10.0% and preferablyfrom about 0.02% to 5.0% fluoride releasing agent, (iii) a dispensingcontainer comprising at least two discreet compartments each with anoutlet end, the first compartment storing the first component whichincludes soluble calcium salt and the second compartment storing thesecond component which includes soluble phosphate salt together with thefluoride source, (iv) a closure mechanism for closing the compartments;and (v) wherein when the two components are mixed the pH in betweenabout 4.5 and 10.0 and preferably between about 5.5 and 7.0.

A plurality of packaging methods may be employed in order to separatelycontain or store the two components and provide effective dispensingthereof into the oral cavity.

Thus, the two components of a toothpaste, gel, cream, or the like, maybe simultaneously dispensed from separate collapsible tubes preferablymade of plastic, a plastic and metal laminate, etc. For convenience andin order to aid in dispensing substantially equal amounts of thecomponents, the tubes may be held together by banding or cementing,preferably along the corresponding ventral sides of the tubes.

In another embodiment the two tubes may be constructed to have abutting,preferably flats sidewall portions. In the forgoing embodiments themouths of the tubes are usually sufficiently close so that sufficientquantities of the components of the toothpaste or gel may besimultaneously dispensed directly on the toothbrush with the tubes thebeing capped separately.

Alternatively, another packaging method comprises loading each componentof the paste or gel into separate compartments of the same collapsiblecomposite tube, joined by a common orifice. Such composite tube hascompartments separated by a divider which is firmly attached alongsubstantially diametrically opposed portions of the sidewall, andcorresponding portions of the head structure of the tube. The dividermay be glued or welded to the sidewall and head structure of the tubeduring manufacture of the latter. The divider is preferably providedwith a protruding portion which extends into the mouth of the tube untilits edge is substantially flush with the rim of the mouth. Thus, adivider forms with the sidewall two separate compartments ofsubstantially the same volume for storage of the cationic and aniomiccomponents, respectively.

In another alternative packaging method, the two tubes are "concentric".An inner tube lies within and parallel with an outer tube. The mouths ofthe tubes abut at the same point. Protrusions or the like are insertedbetween the inner and outer tubes so that the component contained in theouter tube can pass through an available space between the mouth ofouter tube and the mouth of the inner tube. The closures of thistube-within-a-tube, (which can screw on the outer tube or simply be heldby pressure), may, but does not have to be, equipped with an interiorprotrusion to fit in the inner tube in order to prevent prematureintermixing of the two components at the mouth of the tube.

The tubes of all the above embodiments are usually filled from thebottom and are subsequently sealed together by conventional techniques.

Another alternative packaging arrangement comprises of a pressurizedcontainer which is provided with two compartments and two spouts. Theinternal pressure of the compartments is maintained by a pressurizedgas, i e., nitrogen, at the bottom of each compartment. Operation of amechanical actuator actuates valves which release the contents of thecompartments through the spouts causing discharge of the paste or gelcomponents onto a brush. The mouthwash or rinse and similar liquidembodiments are maintained in a manner similar to the pastes or gels inthat during storage, each of the components are maintained separate fromone another to prevent premature reactions. Upon dispensing, thecomponents mix and react in the oral cavity to effect remineralizationof dental enamel. The liquid components can therefore be stored each inseparate compartments of a dual-compartment dispenser. The dispenserusually includes a closure system comprising for example, an inclinedcrown portion, at least two pouring spouts extending upwardly from anupper surface of the crown portion and a cover for securement to thecrown portion. The cover is provided with closure means, for example,depending plugs, to close the closure. Each pouring spout is preferablyprovided with a vent opening in addition to product orifices in thespouts. The orifices can be positioned close together on the crown, allof which assists in achieving control over pouring. Transparentcontainers have proven to be the most satisfactory. Transparency aids aperson's ability to accurately and controllably dispense relativelyequal volumes from a dual-compartment dispenser. Transparent walledcontainers also serve as a window function for gauging the amounts ofliquid remaining in the dispenser. The walls of the containers can bescribed or otherwise calibrated to assist in dispensing the correctremineralizing amount of product.

While applicants do not wish the scope of the present invention to belimited by theory, it is believed that the calcium, phosphate, andfluoride ions diffuse through the tooth surface to the demineralizedsubsurface and precipitate in the demineralized subsurface where theyremineralize the tooth structure. This is surprising because sufficientcalcium, phosphate, and fluoride ions remain soluble for a period oftime sufficient to permit their diffusion into the demineralizedsubsurface of the dental enamel. This is accomplished by combining theparticular ions just prior to their application to the tooth in asolution having a pH of about 4.5 to 10 and preferably from about 5.5 to7 at which pH enough of the calcium, phosphate, and fluoride ions remainsoluble for the period of time required to remineralize the lesions ofthe dental enamel. As hereinbefore described, the calcium and phosphateions are stored separately to avoid the premature precipitation ofcalcium phosphate.

Chemically equivalent concentrations of the first and second solutionsare not necessary as long as the molar ratio of calcium and phosphateions in the mixture is from about 0.01 to up to 100 to 1. It ispreferred that the ratio is from about 0.2 to 1 up to 5 to 1, and it ismost preferred that the ratio is about 1.67 to 1, the ratio of calciumto phosphate in natural tooth enamel (hydroxyapatite).

While completely aqueous solutions are preferred in the presentinventions non-aqueous solvents may be employed in combination withwater. For example, suitable nonaqueous solvents include ethyl alcohol,glycerine and propylene glycol. Solvent systems suitable for use in thepresent invention are those which are capable of dissolving the saltsemployed in the invention and which are safe for use in the mouth.

With regard to the period of time of exposure of the solutions to theteeth, it is necessary that the length of time be great enough to allowdiffusion of the ions into the demineralized subsurface. At least aboutten seconds are required for this diffusion. The solution is preferablyapplied to the teeth for from about 10 seconds to about 5 minutes. ThepH of the solution remains relatively constant after its introductioninto the oral cavity. Calcium phosphate readily precipitates at this pH,but most surprisingly while some of the precipitation may occurimmediately and some small amount even before application to the teeth,sufficient calcium, phosphate and fluoride ions remain in solution todiffuse into the teeth and remineralize the demineralized dental enamel.It is believed that the ability of the solutions to provide ions forremineralization is greatest upon their first introduction into the oralcavity, thereafter decreasing.

The time period between the mixing of the first and second solutions andthe application of the mixture to the teeth should not exceed 1 minute,and preferably is less than 1 minute. With a toothpaste, gel, and thelike, mixing is achieved on the surface to the teeth while brushing. Theessence of the present invention lies in the mixing of components andthe quick and timely application of the resulting solution which willprecipitate calcium phosphate, calcium fluoride, and calciumfluoro-apatite in the subsurface enamel of the teeth. Before suchprecipitation occurs, the mixture comprising the solution must quicklybe applied to the teeth. Surprisingly, the solution can have a pH ofabout 4.5 to 10, but preferably about 5.5 to 7 to achieve this result.At a pH below about 3, demineralization occurs rapidly. A pH below 2.5is generally undesirable from a safety standpoint.

The pH of the solutions of the present invention may be adjusted to thepH desired by methods well known in the art. The pH may be lowered bythe addition of any acid which is safe for use in the oral cavity andwhich yields the desired pH at the amount employed. Examples of suitableacids are acetic acid, phosphoric acid, hydrochloric acid, citric acidand malic acid.

The following Examples illustrate the invention: In the Examples andelsewhere herein parts and percent are by weight unless otherwisestated.

EXAMPLE 1

Artificial lesions, about 50 u deep, were formed in one surface ofbovine enamel chips using a demineralizing Carbopol gel, which was usedto treat the specimens for 72 hours. The surface hardness of the surfaceto be treated was then measured.

The regimen cycle consisted of a 30 minute demineralization in astandard demineralizing solution followed by a 5 minute treatment of thetest products diluted 1 part product to two parts human saliva, followedby a 60 minute remineralization in human saliva. Overnight, which wasevery fifth cycle, the specimens were kept with a layer of saliva andstored in a cold room. The test ran for three days, from a total of 15demineralization:treatment:remineralization cycles.

For the treatment cycle, the two parts of the remineralizing test agentsof the example were separately diluted 1 part product to 2 parts salivaand mixed together immediately before immersion of the enamel specimens.

The two part oral remineralizing treatment was prepared as follows:

    ______________________________________                   Part A    Part B    ______________________________________    Water            71          66.45    Calcium nitrate   4           0.00    Dipotassium phosphate         8.00    Sodium fluoride               0.55    Glycerin         25          25.00    Acetic acid      To adjust pH of                     A & B mixture of                     5.5 immediately                     after mixing.    ______________________________________

Hardness Increase Due to Treatment (Vickers Hardness Units)

    ______________________________________                            1200 ppm                            Fluoride at    Example 1    Crest      pH 5.5   Placebo    ______________________________________     5 cycles            17.0 + 1.9                     11.8 + 1.4    10 cycles            23.6 + 1.4                     13.0 + 3.6 13.7 + 2.3                                       3.9 + 0.7    15 cycles            34.8 + 2.8                     11.2 + 1.7    20 cycles            48.2 + 2.8                     17.5 + 2.2    ______________________________________

Fluoride Increase Due to Treatment (ug/cm³)

    ______________________________________                             1200 ppm                             Fluoride at            Example 1                   Crest     pH 5.5   Placebo    ______________________________________     5 cycles 2433     1879    10 cycles 3523     2082      2928   244    15 cycles 4431     2196    20 cycles 4749     2964    ______________________________________

The results show much greater remineralization, as measured by hardnessincrease and fluoride uptake, due to treatment with the product ofExample 1 than Crest, fluoride solution or placebo.

EXAMPLES 2, 3, and 4

Two part oral remineralizing treatments were prepared as follows:

    ______________________________________            Example 2     Example 3    Example 4             A   B        A     B      A   B    ______________________________________    Water      73    66.45    74  66.45  73  66.45    Calcium     2     0.00     1   0.00  2    0.00    nitrate    Dipotassium       8.00         8.00       8.00    phosphate    Sodium            0.55         0.55       0.55    fluoride    Glycerin   25    25.00    25  25.00  25  25.00    Acetic acid              To adjust pH of                          To adjust pH of                                     To adjust the              A & B       A & B      pH of A & B              mixture to  mixture to mixture              5.5         5.5        to 4.5              immediately immediately                                     immediately              after mixing.                          after mixing.                                     after mixing.    ______________________________________

The same cyclic regimen used to evaluate Example 1 was used to evaluatethe remineralizing efficacy of the above formulations compared withCrest. In this study 15 cycles were used.

Hardness and Fluoride Increase Due to Treatment

    ______________________________________    Example 2    Example 3  Example 4 Crest    ______________________________________    Hardness           45.1 + 2.9                     37.6 + 2.4 32.7 + 2.5                                        14.2 + 1.8    increase    Fluoride           4677 + 219                     5686 + 138 4495 + 343                                        2099 + 182    uptake    ______________________________________

The results show much greater remineralization, as measured by hardnessincrease and fluoride uptake, due to treatment with Examples 2, 3, and 4of the invention than Crest.

EXAMPLES 5, 6, 7, 8, 9 and 10

Two part oral remineralizing treatments were prepared as follows:

    __________________________________________________________________________              Example 5                      Example 6                              Example 7                                       Example 8                                               Example 9                                                       Example 10              A  B    A  B    A  B     A  B    A  B    A  B    __________________________________________________________________________    Water     71.2                 70.45                      67.4                         66.86                              67.4                                 66.45 63.6                                          62.45                                               67.4                                                  66.45                                                       67.4                                                          66.45    Calcium nitrate               3.8                  0.00                       7.6                          0.00                               7.6                                  0.00 11.4                                           0.00                                               11.4                                                   0.00                                                        7.6                                                           0.00    Dipotassium phosphate                  4.00    8.00    8.00    12.00    8.00    8.00    Sodium fluoride                  0.55    0.14    0.55     0.55    0.55    0.55    Glycerin  25.0                 25.00                      25.0                         25.00                              25.0                                 25.00 25.0                                          25.00                                               25.0                                                  25.00                                                       25.0                                                          25.00    Acetic acid              To adjust pH of                      To adjust pH of                              To adjust the pH                                       To adjust pH of                                               To adjust pH                                                       To adjust the pH of              A & B mixture to                      A & B mixture to                              of A & B mixture                                       A & B mixture to                                               A & B mixture                                                       A & B mixture to              5.5 immediately                      5.5 immediately                              to 4.5 immediately                                       5.5 immediately                                               5.5 immediately                                                       4.5 immediately              after mixing.                      after mixing.                              after mixing.                                       after mixing.                                               after mixing.                                                       after    __________________________________________________________________________                                                       mixing.

The same cyclic regimen used to evaluate Examples 1-4 was used toevaluate the remineralizing efficacy of the Examples 5-10 compared withCrest. In this study 15 cycles were used.

Hardness Increase Due to Treatment Vickers Hardness Units

    ______________________________________                Hardness increase    ______________________________________    Example 5     97 + 6    Example 6     97 + 6    Example 7     95 + 2    Example 8     84 + 5    Example 9     83 + 5    Example 10    82 + 3    Crest         20 + 2    ______________________________________

The results show much greater remineralization, as measured by hardnessincreases due to treatment with Examples 5-10 of the invention thanCrest. Example 6 shows that even when the fluoride concentration islowered to supply only 27 percent of that supplied by Crest (i.e. 275ppm versus 1150 ppm) much higher levels of remineralization are stillachieved.

Examples 11-16 illustrate various embodiments remineralizing toothpasteformulations of the invention as follows:

    ______________________________________           Example 11                     Example 12 Example 13             A      B        A    B     A     B    ______________________________________    Glycerin 10.0   10.0     5.0  4.0   6.0   6.0    Sorbitol 40.0   40.0     30.0 30.0  34.0  30.0    Water    18.5   19.32    17.9 14.82 32.3  29.5    Silica abrasive             15.0   15.0     0.0  0.0   10.0  5.0    Silica thickener             8.0    8.0      0.0  0.0   8.0   5.0    DCPDH    0.0    0.0      40.0 0.0   0.0   0.0    Calcium nitrate             5.0    0.0      3.5  0.0   6.0   0.0    Monosodium             0.0    3.7      0.0  6.5   0.0   10.0    phosphate    Sodium meta-             0.0    0.0      0.0  40.0  0.0   10.0    phosphate    CMC      1.0    1.0      1.2  1.5   1.4   1.5    Sodium Lauryl             1.5    1.5      1.2  1.8   1.3   1.5    sulfate    Sodium   0.0    0.48     0.0  0.48  0.0   0.1    fluoride    Flavor   0.8    0.8      0.9  0.7   0.7   1.0    Saccharin             0.2    0.2      0.3  0.2   0.3   0.4    ______________________________________           Example 14                     Example 15 Example 16             A      B        A    B     A     B    ______________________________________    Glycerin 10.0   10.0     5.0  4.0   6.0   6.0    Sorbitol 40.0   40.0     30.0 30.0  34.0  30.0    Water    18.5   19.32    17.9 14.82 32.3  29.5    Silica abrasive             15.0   15.0     0.0  0.0   10.0  5.0    Silica thickener             8.0    8.0      0.0  0.0   8.0   5.0    DCPDH    0.0    0.0      40.0 0.0   0.0   0.0    Calcium nitrate             5.0    0.0      3.5  0.0   6.0   0.0    Monosodium             0.0    3.7      0.0  6.5   0.0   10.0    phosphate    Sodium meta-             0.0    0.0      1.2  1.5   1.4   1.5    phosphate    Sodium Lauryl             1.5    1.5      1.2  1.8   1.3   1.5    sulfate    Sodium   0.0    1.81     0.0  0.0   0.0   0.0    fluoride    Sodium MFP             0.0    0.0      0.0  1.52  0.0   0.2    Flavor   0.8    0.8      0.9  0.7   0.7   1.0    Saccharin             0.2    0.2      0.3  0.2   0.3   0.4    ______________________________________

Example 17 illustrates an embodiment of a remineralizing Mouthwashformulation as follows:

    ______________________________________                     EXAMPLE 17                     Part A                           Part B    ______________________________________    Glycerin           10.000  10.0    Ethanol            20.000  20.0    Sodium fluoride    0.055   0.00    Calcium nitrate    0.000   5.00    Dipotassium phosphate                       5.000   0.00    Monopotassiumphosphate                       0.000   0.00    Water              QS      QS    ______________________________________

What is claimed is:
 1. A method for remineralizing at least one lesionformed in a subsurface of at least one tooth and/or mineralizing atleast one exposed dentinal tubule in said subsurface of said tooth,consisting essentially of:(i) dispensing a first discrete componentconsisting essentially of from about 0.05% to 15.0% of at least onewater-soluble calcium salt, wherein the calcium salt is calcium chlorideor calcium nitrate; (ii) dispensing a second discrete componentconsisting essentially of from about 0.05% to 15.0% of at least onewater-soluble phosphate salt and from about 0.01% to 5.0% of at leastone water-soluble fluoride salt, wherein the first and second componentseach have a pH in water such that a mixed aqueous solution formed bymixing the first and second components with water and/or saliva has a pHof from 4.5 to 10.0; (iii) mixing said first discrete component and saidsecond discrete component with water and/or saliva to form a mixedaqueous solution having a pH of from 4.5 to 10 and consistingessentially of calcium ions released by the calcium salt, phosphate ionsreleased by the phosphate salt and fluoride ions released by thefluoride salt; and (iv) immediately after step (iii), applying saidmixed aqueous solution to the at least one tooth for a sufficient timethat the calcium and phosphate ions diffuse into the subsurface of saidtooth and subsequently precipitate to form hydroxyapatite, therebyremineralizing the at least one lesion and/or mineralizing the at leastone exposed dentinal tubule.
 2. The method according to claim 1 whereinsaid first and second components are a paste, a gel, or a professionalgel and are extruded together onto a toothbrush.
 3. The method accordingto claim 1 wherein the brushing takes place within about one minuteafter extruding said components and placing them onto the toothbrush. 4.The method according to claim 1 wherein the period of application ofcalcium and phosphate ions to the teeth is from about 10 seconds up to 5minutes.
 5. The method according to claim 1 wherein the first componentis comprised of from about 0.10% to 10.0% of said calcium salt.
 6. Themethod according to claim 1 wherein the second component is comprised offrom about 0.10% to 10.0% of said phosphate salt.
 7. The methodaccording to claim 1 wherein the second component contains from about0.02% to 2.0% of said water-soluble fluoride salt.
 8. The methodaccording to claim 1 wherein the resulting mixture has a pH of fromabout 5.5 to 7.0.
 9. The method according to claim 1 wherein the molarratio of calcium and phosphate ions in the two components is from about0.01 to 1 up to 100.0 to
 1. 10. The method according to claim 1 whereinthe molar ratio of calcium and phosphate ions in the two components isfrom about 0.2 to 1 up to 5.0 to
 1. 11. The method according to claim 1wherein the first component contains from about 100 ppm to 35,000 ppmcalcium ions, and the second component contains from about 250 ppm to40,000 ppm phosphate ions and from about 20 ppm to 5,000 ppm fluorideions.
 12. The method according to claim 1, wherein the phosphate salt isselected from the group consisting of dipotassium phosphate, sodiummetaphosphate, and monosodium phosphate.
 13. The method according toclaim 1, wherein the phosphate salt is selected from the groupconsisting of alkali metal salts of orthophosphoric acid and ammoniumsalts of orthophosphoric acid.
 14. The method according to claim 13,wherein the phosphate salt is selected from the group consisting ofpotassium orthophosphate, sodium orthophosphate, and ammoniumorthophosphate.
 15. A method for remineralizing at least one lesionformed in a subsurface of at least one tooth and/or mineralizing atleast one exposed dentinal tubule in said subsurface of said tooth,comprising the steps of:(1) providing a two-component product consistingessentially of:(a) a first discrete component consisting essentially offrom about 0.05% to 15.0% by weight of at least one water-solublecalcium salt; and (b) a second discrete component consisting essentiallyof from about 0.05% to 15.0% by weight of at least one water-solublephosphate salt and from about 0.01% to 5.0% by weight of at least onewater-soluble fluoride salt, wherein the first and second discretecomponents each have a pH in water such that a mixed aqueous solutionformed by mixing said first and second components with water and/orsaliva has a pH of from 4.5 to 10.0, further wherein the first andsecond discrete components are simultaneously released from said productwhen said product is mixed with water and/or saliva; (2) mixing saidproduct with water and/or saliva so as to cause the first and seconddiscrete components to be simultaneously released from the product intothe water and/or saliva, thereby forming a mixed aqueous solution havinga pH of from 4.5 to 10.0 and consisting essentially of calcium ionsreleased by the calcium salt, phosphate ions released by the phosphatesalt and fluoride ions released by the fluoride salt; and (3)immediately after step (2), applying the mixed aqueous solution to asurface of said at least one tooth, whereby an amount of said calciumions, an amount of said phosphate ions and an amount of said fluorideions diffuse through the surface of said tooth to the subsurface of saidtooth, where the diffused calcium ions, diffused phosphate ions and thediffused fluoride ions react together to form an insoluble precipitateon said lesion and/or said exposed dentinal tubule, therebyremineralizing said lesion and/or mineralizing said exposed dentinaltubule.
 16. The method according to claim 15, wherein said calcium saltis calcium chloride or calcium nitrate.